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Effect of SSRIs and SNRIs on Nocturnal Urinary Frequency

Medarov BI, Chaudhry H, Sun JH, Rane N, Judson MA

Annals of Pharmacotherapy, Volume 50, Issue 6, June 2016, Pages 471 - 4

Commented by Prof. Karl-Erik Andersson
Do SSRIs and SNRIs have any effects on nocturia?

Depression and nocturia appear to be frequently comorbid and a bidirectional association between depression and nocturia.has been suggested (Breyer et al., 2013). Therapeutically, tricyclic antidepressants, e.g., imipramine and amitriptyline have been used for treatment of overactive bladder (OAB) symptoms, including nocturia. However, imipramine is the only drug that has been widely used clinically. Even if imipramine may have positive effects on nocturia, this has not been documented in randomized controlled trials, and the drug has not been recommended by the International Consultation on Incontinence (ICI) for OAB treatment due to the risk of serious cardiovascular effects (Andersson et al., 2013). Imipramine has complex pharmacological effects, including marked systemic antimuscarinic actions and blockade of the reuptake of serotonin and noradrenaline. Its mode of action in OAB has not been established, but a main contribution to its efficacy may be the antimuscarinic effect.

Other drugs with antidepressant actions, but largely lacking antimuscarinic effects, are the selective serotonin re-uptake inhibitors (SSRIs) and the serotonin–norepinephrine reuptake inhibitors (SNRIs). SSRIs (box 1) are believed to increase the extracellular level of serotonin by limiting its reabsorption into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for other monoamine transporters, with pure SSRIs having only weak affinity for the norepinephrine and dopamine transporters. SNRIs) are potent inhibitors of the reuptake of both serotonin and norepinephrine. In contrast to the more widely used SSRIs the SNRIs (box 2) act upon serotonin alone.

The effects of SSRIs and SNRIs on OAB symptoms, specifically nocturia, have not been established. In a retrospective study, Medarov et al. (2016), evaluated the impact of these classes of drugs on nocturnal urinary frequency in 316 individuals ≥18 years old referred for nocturnal polysomnography: 94 in the SSRI/SNRI group and 222 controls. They found no statistically significant difference in nocturnal urinary frequency between those on SSRI/SNRI therapy and the control group. On the other hand, a comparison between sertraline (SSRI) and duloxetine (SNRI) users showed that the degree of urinary frequency was higher in subjects using sertraline (0.61 bathroom visits/night) compared with duloxetine (0.18 visits/night, 2-tailed P = 0.04). Even if the sample size did not allow conclusive comparison of either the SSRI or the SNRI group with the control group, it was concluded that the SSRIs and SNRIs may have an opposite effect on nocturnal frequency. If such a difference exists, is this be of clinical relevance? Is there a therapeutic opportunity for SNRIs?

In a systematic review focused on the relationship between nocturia and depression/anxiety, Movig et al. (2008) concluded that exposure to SSRIs was associated with an increased risk for developing urinary incontinence. They found that approximately 15 out of 1000 patients treated per year with an SSRI developed urinary incontinence, and that the elderly were at the highest risk. Patients using sertraline more frequently developed incontinence when compared with users of fluvoxamine, fluoxetine or paroxetine.

In a placebo-controlled study duloxetine hydrochloride (SNRI) was shown to have efficacy in patients with OAB (Steers et al., 2007). The number of micturition episodes, the primary outcome, was reduced by 2 in the duloxetine arm and by 0.5 in the placebo arm. Episodes of urgency incontinence were also significantly reduced.  However, there seemed to be no effect on nocturia: reductions in nocturic episodes were significantly greater with placebo than with duloxetine, with virtually no difference in nocturia from baseline to endpoint with duloxetine. Contributing to this results may be the fact that at baseline, 120 of 306 (39.2%) patients had only one or fewer nocturic episodes/24 h.

Di Rezze et al. (2012) reported positive effects of duloxetine in patients with OAB symptoms and multiple sclerosis; effects on nocturia were not specifically analysed. The effects of milnacipran hydrochloride (SNRI), and paroxetine hydrochloride (SSRI), were analysed in a prospective open trial in neurogenic OAB-patients. Milnacipran reduced daytime urinary frequency, improved the quality of life index and increased bladder capacity as shown in urodynamic studies. No such changes were noted in the other categories of the lower urinary tract symptoms questionnaire or urodynamic studies, or in the paroxetine group (Sakakibara et al., 2008). 

Based on available evidence, including the study by Medarov et al. (2016), the effects of SSRIs and SNRIs on nocturnal voiding are still unclear. Patients with depression or anxiety treated with SSRIs or SNRIs may or may not develop nocturia. It cannot be excluded that SSRIs and SNRIs have opposite effects, SSRIs (e.g. sertraline) worsening and SNRIs (duloxetine?) improving the frequency of nocturnal voiding. However, from a nocturia treatment aspect SNRIs do not seem to offer an attractive alternative considering the questionable efficacy (Steers et al., 2007) vs the frequently occurring adverse effects (Wernicke et al., 2005).               

Box 1. Commonly used SSRIs
Citalopram 
Fluvoxamine
Escitalopram
Paroxetine
Sertraline
Fluoxetine

Box 2. Commonly used SNRIs
Desvenlafaxine
Duloxetine 
Venlafaxine 
Milnacipran 
Levomilnacipran 

Abstract
 

BACKGROUND:

Existing data suggest that selective serotonin uptake inhibitors (SSRIs) may have an impact on urinary frequency.

OBJECTIVE:

To evaluate the impact of SSRIs and selective noradrenaline reuptake inhibitors (SNRIs) on nocturnal urinary frequency.

METHODS:

This was a retrospective study comparing nocturnal urinary frequency in individuals on SSRI or SNRI therapy versus no therapy during nocturnal polysomnography in a 14-month period at a sleep center.

RESULTS:

A total of 316 individuals were studied: 94 in the SSRI/SNRI group and 222 controls. No statistically significant difference was found in nocturnal urinary frequency between those on SSRI/SNRI therapy and the control group (0.40 vs 0.34 bathroom visits/night, P = 0.40). The degree of urinary frequency was higher in sertraline users (0.61 bathroom visits/night) compared with duloxetine users (0.18 visits/night, 2-tailed P = 0.04). A post hoc analysis suggested that the difference between these 2 agents is a class effect (SSRIs vs SNRIs, 2-tailed P = 0.03). The sample size did not allow conclusive comparison of either the SSRI or the SNRI group with the control group.

CONCLUSION:

SSRI/SNRI agents as a combined group do not appear to have a significant impact on nocturnal urinary frequency. The SSRIs and SNRIs may have an opposite effect on nocturnal frequency.

References

  1. Breyer BN, Shindel AW, Erickson BA, Blaschko SD, Steers WD, Rosen RC. The association of depression, anxiety and nocturia: a systematic review. J Urol. 2013 Sep;190(3):953-7. 
  2. Andersson K-E, Chapple CR, Cardozo L et al. Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo , Khoury S, Wein A (eds). Incontinence, 5th International Consultation on Incontinence. ICUD-EAU, International Consultation on Urological Diseases – European Association of Urology, 2013; 623–728.
  3. Medarov BI, Chaudhry H, Sun JH, Rane N, Judson MA. Effect of SSRIs and SNRIs on Nocturnal Urinary Frequency. Ann Pharmacother. 2016 Jun;50(6):471-4.
  4. Steers WD, Herschorn S, Kreder KJ, Moore K, Strohbehn K, Yalcin I, Bump RC; Duloxetine OAB Study Group. Duloxetine compared with placebo for treating women with symptoms of overactive bladder. U Int. 2007 Aug;100(2):337-45. 
  5. Di Rezze S, Frasca V, Inghilleri M, Durastanti V, Cortese A, Giacomelli E, Millefiorini E. Duloxetine for the treatment of overactive bladder syndrome in multiple sclerosis: a pilot study. Clin Neuropharmacol. 2012 Sep-Oct;35(5):231-4.
  6. Sakakibara R, Ito T, Uchiyama T, Awa Y, Yamaguchi C, Hattori T. Effects of milnacipran and paroxetine on overactive bladder due to neurologic diseases: a urodynamic assessment. Urol Int. 2008;81(3):335-9.
  7. Movig KL, Leufkens HG, Belitser SV, Lenderink AW, Egberts AC. Selective serotonin reuptake inhibitor-induced urinary incontinence. Pharmacoepidemiol Drug Saf. 2002 Jun;11(4):271-9.
  8. Wernicke JF, Gahimer J, Yalcin I, Wulster-Radcliffe M, Viktrup L. Safety and adverse event profile of duloxetine. Expert Opin Drug Saf. 2005 Nov;4(6):987-93.


K-E Andersson, MD, PhD

Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA, and Institute of Clinical Medicine, Department of Obstetrics and Gynecology, Aarhus University, Aarhus Denmark

Correspondence:

Institute of Clinical Medicine, Department of Obstetrics and Gynecology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK 8200 Aarhus N, Denmark.

tel +510-717-3765

e-mail:
karl-erik.andersson@med.lu.se
kea@aias.au.dk
keanders@wakehealth.edu

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